10, 11-dihydro-or-5-[3-(n-methyl-n-thiourethane amino)-propylidene-or-propyl-]5h-dibenzo cycloheptenes



United States Patent 3,379,750 10,11 DIHYDRO- 0R [3 (N METHYL N- THIOURETHANE AMINO)-PROPYLIDENE- 0R -PROPYL-]5H-DIBENZO CYCLOHEPTENES Janos Kollonitsch, Westfield, N.J., assignor to Merck 8: Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Continuation-impart of application Ser. No. 194,660, May 14, 1962. This application Mar. 10, 1965, Ser. No. 438,780

17 Claims. (Cl. 260-455) This application is a continuation-in-part of my copending application, Ser. No. 194,660, filed May 14, 1962 and now abandoned.

This invention relates to a novel method for making derivatives of dibenzocycloheptenes, and more particularly the invention relates to a method of making 5H- dibenzo[a,d]-10,1l-dihydrocycloheptenes and SH-dibenzo [a,d]cycloheptenes which are substituted at the S-carbon atom with a secondary aminopropyl or secondary aminopropylidene radical. The invention also relates to intermediates which are useful in preparing the above compounds and a method of preparing the same.

The end compounds of the invention are useful in the treatment of mental health conditions as they are antidepressants and serve as mood elevators or psychic energizers. The compounds are preferably administered in the form of their acid addition salts and these salts are included in the scope of this invention.

The end compounds formed by the method of the invention may be represented by the following general formulas:

HH HH H CH2 CHrCHnNHCHs H H H H wherein X and X may be similar or dissimilar and are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower alkenyl, haloloweralkyl, phenyl or substituted phenyl, an acyl group having up to 4 carbon atoms, haloacyl having up to 4 carbon atoms, a loweralkylsulfonylamino, halogen, hydroxyl, haloloweralkoxy, cyano, carboxy, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, loweralkoxycarbonyl, mercapto, loweralkylmercapto, haloloweralkylmercapto, loweralkyl- "Ice sulfonyl, haloloweralkylsulfonyl, sulfamyl, loweralkylsulfamyl, diloweralkylsulfamyl; more than one of these substituents may be on each benzenoid ring.

Representative compounds which may be prepared in accordance with the intsant invention include: 5-( 3-methylaminopropyl) -5H-dibenzo [a,d] cycloheptene 10,1 l-dihydro-S- 3-methylaminopropyl) -5H-dibenzo [a,d]-cycloheptene 5-(3-methylaminopropylidene)-SH-dibenzo[a,d]

cycloheptene 10,1 l-dihydro-S- 3-methylaminopropylidene) -5H- dibenzo-[a,d]cycloheptene 3-chloro-5-(3-methylaminopropyl)-5H-dibenzo[a,d]

cycloheptene 3-methyl-5-(3-methylaminopropylidene)-5H-dibenzo [a,d]cycloheptene 5- 3 -methylaminopropyl -3 -methylsulfonyl-5H-dib enzo [a,d] cycloheptene 5- 3-methylaminopropylidene -3-methy1sulfonyl-5H- dibenzo [a,d] cycloheptene 3-dimethylsulfamoyl-5- 3-methylaminopropyl) -5H- dib enzo a,d] cycloheptene 10,1 1-dihydro-3 -dimethylsulf am oyl-5 3 -methylaminopropylidene) -5H-dibenzo [a,d] cycloheptene It should be noted that with regard to the process described herein, the essence of the invention resides in the conversion of the dimethylaminopropylidene (propyl) side chain to the monomethylaminopropylidene (propyl) substituent and not in the particular groups which may be attached to either or both of the benzene moieties. Accordingly, the process of the invention may beutilized for the preparation of nuclearly unsubstituted as well as nuclearly substituted derivatives by employing the appropriate unsubstituted or nuclearly substituted tertiaryaminopropylidene (propyl) compound. It will be readily recognized by those skilled in the art that the process may be utilized for the preparation of those nuclearly substituted compounds wherein the nuclear substituents remain unaiiected during the reaction and the nuclear substituents mentioned hereinabove are merely representative and are not to be construed as limiting the invention.

The method of the present invention may be illustrated schematically by the following flow sheet in which the dotted lines indicate the compound may be saturated or unsaturated at the indicated positions, X and X are as previously defined and R is alkyl, aryl, aralkyl or alkaryl.

Hydrolysis critical. Thus, the reaction may be carried out at room or elevated temperatures employing other inert, organic solvents capable of solubilizing the intermediate thiourethane such as toluene, heptene, hexane, chloroform,

carbon tetrachloride and tetrahydrofuran.

The urethane intermediate thus produced is then hydrolyzed to convert the substituted thiocarbamyl group of the thiourethane to a hydrogen atom. It is preferred,

| however, to first oxidize the thiourethane prior to carrying out the hydrolysis. The oxidation may be carried out employing any of the conventional oxidizing agents such as hydrogen peroxide, peracetic acid, perbenzoic acid, chromic acid and potassium permanganate. The hydrolysis is gg zg i i l i' g g g g g fiz ig ig g g if; can then be effected in either an acidic or basic medium, process, it is not critical which particular R group is or m Water f whet? IS deslred to hydrolyze utilized to form the intermediate thiourethane and the P thlourethane lthout sublectmg i Same: to Wildachoice thereof is subject only to the limitations of ease of the hydrolysis should be effected in a basic medium, hydrolysis and other practical and economical considerau h as Sodlum llydroxldfb 1n the Presence of a metal tions However, the Preferred groups are lower alkyl such as lead or silver, which will react with the mercaptan having up to 6 carbon atoms, phenyl, tolyl, p-chloroform an insoluble p phenyl and benzyL The product of the hydrolysis is the desired secondary The method of the present invention begins with the aminopropylidene or secondary aminopropyl derivative known aminopropylidene or aminopropyl compounds of a SH-dibenzo[a,d]cycl0heptene or SH-dibenzo which are described in several places in the literature, [a,b]-l0,ll-dihydrocycloheptene. in British Patents 358,187 and ,188, in the The examples which follow will further illustrate the Journal of Organic Chemistry, volume 27, page 230 invention (1962), and elsewhere. These compounds are prepared from, for example, the known 5H-dibenzo[a,d]cyclo Example y y p y hepten-S-ones and 5H dibenzo[a,d1 10,11 dihydro- )-P P fll y p cyclohepten-S-ones which, in turn, may be prepared by using the process described by A. C. Cope et a1. gof 5-(3-dimeihylaminopfopylidene)-5H-dibBI1ZO in an article entitled, Cyclic Polyolefins, XV, 1- l fil y p 111016) is dissolved in 20 1111- of methylene 2,3,6,-7 dibenzocycloheptatriene, appearing benzene and solution of 2.76 g. (0.025 mole) of methyl in the I.A.C.S., 73, 1673-1678 (1951) and elsewhere, or chlorothiolformate in 10 ml. of benzene is added during the starting compounds, and particularly those having about 15 minutes while the mixture is stirred at room substituents on the benzene rings, y be made y temperature. The solution is refluxed with stirring for 1 /2 lowing the teachings of PP et in article hours, cooled to room temperature, filtered, the filtrate Synthesls of acetamlflo 2353411321110 40 extracted with 2.5 N HCl (3X 25 ml.), washed with tropilidine and Z-acetamrdo 9,9 dimethylfluorene, apwater, dried over Mgsok1 and evaporated in vacuo A i gt i ig' i gg fifi g ss fii igi gfi g the thick, colorless oil rapidly crystallizes. Yield 5.8 g. (69% method of the present invention involves the condensaof theory) For analysls the product i i tion of a dimethylaminopropylidene or dimethylaminofrom 15 of ethanoloto produce of ghstemng propyl derivative of a 5H-dibenzo[a,d] cycloheptene needless 106-108 with a halothiolforrnate to produce a thiourethane inter- Ana1ys1s' C21H21NOS Calcd" 75); i In a typical mm, 5 [3 (N dimethylamino) H, 6.35; N, 4.2; S, 9.60%. Found: C, 75.16; H, 6.36; propylidene] 5H dibenzo[a,d]cycloheptene is reacted 951%- with methyl chlorothiolformate to produce the thiourethane product 5 [3 (N -methyl-N-methylmercapto- Example 2 form lamino ro lidene 5H dibenzo a,d c clohepte r ie and m eth yl chloride. The reaction is mo t \bon- Followmg the Procedure descnbed m Example and i fl i d out i an inert organic Solvent h as substituting the thiolformates enumerated "below for benzene, and at the reflux temperature of the system. methyl chlorothiolformate of Example 1, there are ob- However, neither the temperature or solvent employed is tained the products enumerated below.

Thiotormate Product Ethyl chlorotltiolforrnate 5-[3-(N-methyl-N-ethylmercaptotormylamino)- ropylidene1-5H-dibenzo[a,d]cycloheptene. Octyl chlorothioliormate 5- 3-(N-methyl-N-octylrnercaptotormylamino)- r0py1idene1-5H-dibenzo[a,d]cycloheptene. Methyl bromothioltormate 5E3-(N-methyl-N-methyhnercaptoformylamin0)- propylidene]-5El-dibenzo[a,d]eycloheptene. Phenyl chlorothloliormate 5-13-(N-methyl-N-phenylmercaptoformylamiuo)- ropylidene1-5H-dibenzo[a,d]cycloheptene.

p-Chlorophenylchlorothiolformate 5- 3-(N-methyl-N-p-chlorophenyl-mercaptoformylamino) -propylidene]-5H-dibenzo[a,d]eycloheptene. p-Tolyl chlorothlolformate 5-[3-(N-methyl-N-p-tolylmerca totormylamino)- ropylldene1-5H-dibeuzo'[a,d cycloheptene. Benzyl chlorothlolformate 5- 3-(N-methy1 N -benzy1mercaptotormylamlno)- propylidene]-5H-dibenzo[n,dlcycloheptene.

3 -din1ethylsulfamoyl-5 [3 (N-methyl-N-p-chlorophenylmercaptoformylamino -propylidene] -5H-dibenzo- [a,d] cycloheptene 3 -dimethylsulfamoyl-5 [3 (N-methyl-N-p-tolylmercaptoformylamino) -propylidene] -5H-dibenzo [a,d] cycloheptene 3-dimethylsulfamoyl-5- 3- (N-methyl-N-benzyl- 3-din1ethylsulfamoyl-5 3- (N-methyl-N benzylmercaptoformylamino)-propylidene]-5H-dibenzo- [a,d]cycloheptene Example 5.--5-(3-methylaminopropylidene)-5I-I-dibenzo- [a,d]cycloheptene 1.68 g. of 5-[3-(N-methyl-N-methylmercaptoformylamino) propyliclene] SH-dibenzo[a,d]cycloheptene (0.005 mole) is dissolved with gentle heating in 13 ml. of glacial acetic acid. After cooling to room temperature, 2 ml. of 30% H 0 is added followed by 7 ml. of glacial acetic acid. After standing at room temperature for 21 hours under stirring, a clear, colorless solution is obtained N which is added into 40 ml. of 11.7 N of sodium hydroxide solution (outside cooling) and diluted with 60 ml. of water. The solution is extracted with benzene (40+2 x 20 water. The soluton is extracted with benzene 40+2 20 ml.), the combined benzene layers washed with 2.5 N HCl (25 ml. +3 10 ml.) and the combined HCl extracts are alkalized with 11.7 N NaOH ml.), extracted with ether (2 X ml.), dried with MgSO and evaporated to dryness. 0.60 g. of the product is obtained in the form of a sticky oil. On seeding, it crystallizes. It is characterized by forming its salt with oxalic acid in ethanol. M.P. of the hemi-oxalate, 202-203" C. (dec.).

Example 6 Following the procedure of Example 5, and substituting the products of Examples 2, 3 and 4 for the -5-[3-(N- methyl N methylmerca-ptoformylamino) propylidene]- 5H-di'benzo[a,d]cycloheptene employed in Example 5, there are obtained the fol-lowing products:

5- 3-methylamin'opr'opylidene) 5 H dibenzo[ a,d] cycloheptene 3-chloro-5-( 3-methylaminopropylidene -5H-dibenzo a,d]

cycloheptene 3 -methyl-5- 3 -methylaminopropyl'idene -5 H-dibenzo- [a,d] -'cyclohe'ptene 5- 3 -methylaminopropyl) -3 -methylsulfonyl-5 H-dibenzo- [a,d] -cycloheptene 5 3 -methylaminopropylidene) 3 -methylsulfonyl-5 H-dibenzo[ a,d] cycloheptene 3 -dimethylsulfamoyl-5- 3 -methylaminopropyl) -5 H-di benzo a,d] cycloheptene 3 -dimethylsulfamoyl-5- (3 -methylamin-op ropylidene) -5*H- dibenzo [a,d] cycl-oheptene Example 7.5 ('3-methylaminopropylidene)-3-methylsulfonyl-SH-dibenzo [a,dlcycloheptene' (A) Preparation of 5-[-3-N-methyl-N-methylmercaptoformyl amino) -propylidene] -3 -me thylsulfonyl-5 H-dibenzo- [a,d]cycloheptene.To a suspension of 1.76 g. of 5-(3- dimethylaminopropylidene) -3 -methylsulfonyl-5 H-dibenzo- [a,d] -cycloheptene in 5 ml. of benzene is added a solution of 1:1 g. of methyl thiolchloroformate in 4 m1. of benzene. The mixture is then refluxed with stirring for 90 minutes. The small amount of insoluble material is filtered off and the filtrate extracted with 2.5 H01 (3X8 ml.), washed with water, dried over magnesium sulfate and evaporated in vacuo, yielding the crude thiourethane. After recrystallization from ethanol, the pure thiourethane melt-s at 144- 145 C.

Analysis for C H NO S .Calcd: C, 64.20; H, 5.57; N, 3.4; S, 15.50. Found: C, 63.62; H, 5.39; N, 3.2; S,

(B). Preparation of 5-(S-methylaminopropylidene)-3- methylsulfonyl-SH-dibenzo [a,d] cycloheptene.--5- [3- (N- methyl-N-methylmercaptoformylamino) propylidene1-3- 8 methylsulfonyl-SH-dibenzo[a,d]cycloheptene, 1.06 g., is dissolved in a mixture of 8 ml. of acetic acid and 2 ml. of formic acid. 1 ml. of 30% hydrogen peroxide is then added at 20-25 C., followed with '6 ml. of acetic acid. After standing overnight at room temperature, the mixture is added to 40 ml. of sodium hydroxide while the temperature is kept at 310 C. (ice-cooling). After extraction with 30 ml. of benzene, an oil separates. This is separated from the aqueous phase, then dissolved in 50 ml. of 1 N H01 and basified with dilute sodium hydroxide solution. The base is extracted with benzene (3 30 ml.) and the combined benzene extracts are then re-extracted with 2.5 N HOl (3 30 ml.). The aoidic extract is ba'sitied and the separated base extracted with diethyl ether. The combined ether extracts are dried over magnesium sulfate and evaporated to give 5-(3-methylaminopropylidene)-3-methylsulfonyl 5H dibenzo[a,d]cycloheptene. This is treated with oxalic acid in isopropanol to form the oxalate salt which melts at 204-205 C. (dec.).

Example '8 .-5- 3-methylaminopr-opylidene -5H- dibenzo a,d] cycloheptene (A) Preparation of 5-[3 (N-methyl-N-butylmercaptoformylamino)-propylidene] 5H dibenzo[a,d]cycloheptens-To a solution of 2.77 g. of 5-(3-d-imethylaminopropylidene)d ll-dibenzo[a,d]cycloheptene in 10 ml. of benzene is added a solution of 1.53 g. of butyl thiolchloroformats in 5 ml. of benzene. The mixture is refluxed with stirring for 3 hours, then filtered, after cooling to room temperature, and the filtrate extracted with 2.5 N sulfuric acid, washed with water, dried over magnesium sulfate and evaporated in vacuo, yielding 5-[3-(N-methyl-N butylmercaptoformylamino) propylidene] 5 H dibenzo[a,d]- cycloheptene.

(B) Preparation of 5-(13 -methylarninopropylidene)- 5H-dibenzo[a,d]cycl-oheptene.-To a solution of 1.5 1 g. of S-[S-(N-methyl N butylmercaptoformylamino) -propylidene]-5H-dibenzo[a,d]cycloheptene in =15 ml. of formic acid is added, with cooling (ice-water), 2 ml. of 30% hydrogen peroxide. The solution is left standing at room temperature for 2 days. The solvent is then removed by distillation in vacuo and the residue stirred with 30 ml. of 5 N NaOH for 2 hours, extracted with benzene (40+ 20+20 ml), and the combined benzene extracts reextrac'ted with 2.5 N HCl ('20 ml.+3 X 10 ml.). The HCl extracts are alkalized with 5 N NaOH solution, extracted with ether (3 X 20 m1.), dried with magnesium sulfate and evaporated to dryness, yielding 5-(3-methylaminopropylidene)-5H-dibenzo[a,d]-cycloheptene. This is treated with oxalic acid in ethanol, yielding the hemi-oxalate salt which melts at 202-203 C. (dec.).

Example 9.5-(Ii-methylaminopropyl)-5H-dibe [a,d] cycloheptenei (A) Preparation of 5-[3-(N-methyl-N-phenylmercaptoformylamin'o) propyl] 5H d-ibenzo[a,d]cycloheptene.-To a solution of 13.9 g. of 5-(3-dimethylaminopropyl)-'5H-dibenzo[a,d] cycloheptene in 50 ml. of henzene is added over a period of 20 minutes, a solution of 8.65 g. of phenyl thiolchloroformate in 30 m1. of benzene. The mixture is refluxed with stirring for 1 hour. After cooling to room temperature, the mixture is extracted with 2.5 N I-ICl (3 ml.), washed with water, dried over magnesium sulfate and evaporated to dryness, yielding 5- 3-(N-methyl-N-phenylmercaptoforrnylamino) -pro- (B) Preparation of 5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene.-To a solution of 3.99 g. of 5 [3 (N methyl N phenylmercaptoformylamino) propyl]-5H-dibenzo[a,d] cycloheptene in 25 ml. of formic acid is added 4.5 ml. of 30% hydrogen peroxide, and the mixture left standing at room temperature for 2 days. The solvent is distilled off in vacuo at 30-35 C., the residue diluted with water, alkalized to phenolphthalein with 5 N NaOH and extracted with benzene (3 X 30 ml.). The combined benzene extracts are re-extracted with 9 dilute HCl (4X 25 ml.) and the combined HCl extracts alkalized with 5 N NaOH solution. The product is taken up in diethyl ether (4X ml.), dried over magnesium sulfate and evaporated to dryness, yielding 5-(3-methylaminopropyl) -5H-dibenzo [a,d] cycloheptene.

Example 10.-'-5-(3-methylaminopropylidene) -5H- dibenzo a,d,] cycloheptene (A) Preparation of 5-[3-(N methyl N benzylmercaptoformylamino) propylidene] 5H dibenzo[a,d] cycloheptene.-To 5.54 g. of S-(S-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene, dissolved in ml. of benzene, is added a solution of 3.33 g. of benzyl thiolchloroformate in 20 ml. of benzene. The mixture is refluxed with stirring for 3 hours. The small amount of precipitate is filtered oil, the filtrate extracted with 2.5 N sulfuric acid (5 X 5 ml.'), washed neutral with water, dried over magnesium sulfate and evaporated in vacuo, yielding 5-[3-(N-methyl-Nbenzyhnercaptoformyl amino) -propylidene] -5H-dibejnzo [a,d] cyclohe-ptene.

(B) Preparation of 5-(3-rrrethylaminopropylidene) 5H-dibenzo[a,d]cycloheptene.To 4.11 g. of 5-[3-(N- methyl N benzylmercaptoformylamino)-propylidene]- 5H-dibenzo[a,d]cycloheptene, dissolved in 25 ml. of formic acid, is added 4 ml. of hydrogen peroxide and the mixture allowed to stand at room temperature for 20 hours. After evaporation of the solvent in vacuo, 20 ml. of water is added, followed by the addition of 2.5 N NaOH until a pH of 10 is obtained. The separating oil is extracted with benzene (3x 30 ml.) and the combined benzene extracts re-extracted with 2.5 N HCl. The combined HCl extracts are alkalized with 5 N NaOH and the separating oil product extracted with diethyl ether. The ether extract is dried over magnesium sulfate and evaporated to dryness, yielding 5-(3-methylaminopropylidene -5H-dibenzo- [a,d] cycloheptene.

I claim:

1. A compound selected from the group consisting of compounds having the formula:

wherein X and X' are selected from the group consisting of hydrogen, halogen, loweralkyl, loweralkylsulfonyl, and diloweralkylsulfamyl and R is selected from the group consisting of lower alkyl having up to 6 carbon atoms, phenyl, tolyl, p-chlorophenyl and benzyl.

2. A compound of the formula wherein X and X are selected from the group consisting of hydrogen, halogen, loweralkyl, loweralkylsulfonyl, and diloweralkylsulfamyl and R is selected from the group consisting of lower alkyl having up to 6 carbon atoms, phenyl, tolyl, p-chlorophenyl and benzyl.

3. A compound of the formula wherein X and X are selected from the group consisting of hydrogen, halogen, loweralkyl, loweralkylsulfonyl, and diloweralkylsulfamyl and R is selected from the group consisting of lower alkyl having up to 6 carbon atoms, phenyl, tolyl, p-chlorophenyl and benzyl.

4. A compound of the formula wherein X and X are selected from the group consisting of hydrogen, halogen, loweralkyl, loweralkylsulfonyl, and diloweralkylsulfamyl and R is selected from the group consisting of lower alkyl having up to 6 carbon atoms, phenyl, tolyl, p-chlorophenyl and benzyl. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA: 